Racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, which is known under the name medetomidine, is a selective and potent α2-adrenoceptor agonist. Medetomidine is used as an antihypertensive agent and as a sedative-analgesic agent. This compound also possesses anxiolytic effects and can therefore be used in the treatment of general anxiety, panic disorder and various types of withdrawal symptoms.
The d-enantiomer of medetomidine, the generic name of which is dexmedetomidine, is described in U.S. Pat. No. 4,910,214 as an α2-adrenoceptor agonist for general sedation/analgesia and the treatment of hypertension or anxiety. U.S. Pat. Nos. 5,344,840 and 5,091,402 discuss dexmedetomidine use in perioperative and epidural applications, respectively. When used in perioperative care, dexmedetomidine can reduce the amount of anesthetic necessary to anesthetize a patient. Additionally, U.S. Pat. No. 5,304,569 discusses using dexmedetomidine in treating glaucoma, and U.S. Pat. No. 5,712,301 discusses using dexmedetomidine for preventing neurodegeneration caused by ethanol consumption. U.S. Pat. No. 6,716,867 discloses methods of sedating a patient in an intensive care unit by administering dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the patient.
Dexmedetomidine is administered to a patient in a variety of ways. U.S. Pat. Nos. 4,544,664 and 4,910,214 disclose the administration of dexmedetomidine via parenteral, intravenous, and oral routes. U.S. Pat. No. 4,670,455 describes intramuscular and intravenous administration, while U.S. Pat. Nos. 5,124,157 and 5,217,718 describe a method and device for administering dexmedetomidine through the skin. Additionally, U.S. Pat. No. 5,712,301 states that dexmedetomidine can be administered transmucosally.
Premixed dexmedetomidine solutions are described in U.S. Pat. No. 8,242,158. The premixed dexmedetomidine solutions are packaged in glass vials because of the tendency of dexmedetomidine to be either adsorbed or absorbed by plastic materials. The patent discloses that up to 20% of the dexmedetomidine is lost through adsorption. The patent reports the cause of potency loss in PVC bags and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) during autoclaving was investigated. Related substances testing on autoclaved premixed dexmedetomidine composition filled in PVC and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) revealed that potency drop did not occur due to degradation, because the total percent of impurities was much less than 20%. Loss of potency may be due to either adsorption (restricted to the surface of the bag) and/or absorption (not restricted to the surface) of the drug into the bags. To confirm the absorption/adsorption phenomena, the CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) and PVC bags that showed 20% potency loss were emptied and rinsed with MeOH and the rinse solvent tested for dexmedetomidine. Nearly all the drug was recovered from CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.)—indicating adsorption and only 1% of the drug was recovered from PVC bags—indicating absorption, since drug dissolves in DEHP. The loss of dexmedetomidine can be reduced by including a buffer system in the formulation but even with a buffer drug loss on the order of 10% is experienced. The patent also reported that Vis-IV™ bags (Hospira, Inc., Lake Forrest, Ill.) had higher impurity levels than either the PVC and CR3 elastomer copolyester bags. All of the plastic containers contained more impurities than the glass ampules, vials and syringes tested.
Flexible plastic containers for drugs are preferred because of ease of storage and the inherent non-breakable properties of the flexible plastic containers. Thus, a need continues to exist for a ready-to-use dexmedetomidine solution packaged in flexible plastic containers.